Zinc Deficiency Decreases Neurite Extension via CRMP2 Signal Pathway.

Previous reports indicated that zinc deficiency could increase the risk of infectious diseases and developmental retardation in children. In experimental study, it has been reported that zinc deficiency during the embryonic period inhibited fetal growth, and disturbed neural differentiation and higher brain function later in adulthood. Although it has been suggested that zinc deficiency during development can have significant effects on neuronal differentiation and maturation, the molecular mechanisms of the effects of low zinc on neuronal differentiation during development have not been elucidated in detail. This study was performed to determine the effects of low zinc status on neurite outgrowth and collapsin response mediator protein 2 (CRMP2) signal pathway. Low zinc suppressed neurite outgrowth, and caused increase levels of phosphorylated CRMP2 (pCRMP2) relative to CRMP2, and decrease levels of phosphorylated glycogen synthase kinase 3ß (pGSK3ß) relative to GSK3ß in human neuroblastoma cell line (SH-SY5Y) cells on days 1, 2, and 3 of neuronal differentiation induction. Neurite outgrowth inhibited by low zinc was restored by treatment with the GSK3ß inhibitor CHIR99021. These results suggested that low zinc causes neurite outgrowth inhibition via phosphorylation of CRMP2 by GSK3ß. In conclusion, this study is the first to demonstrate that CRMP signaling is involved in the suppression of neurite outgrowth by low zinc.

Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy.

BACKGROUND: KRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice. METHODS: Cell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test. RESULTS: In this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo. CONCLUSION: Therefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.

Reversible formation and cleavage of Pt→Ag dative bonds in a pre-organized cavity of a luminescent heteropolynuclear platinum(ii) complex.

A U-shaped Pt2Ag2 complex [Pt2Ag2(ppy)2(Ph2pz)4] with a pre-organized cavity (ppy = 2-phenylpridinate and Ph2pz = 3,5-diphenylpyrazolate) and related complexes have been prepared. The Pt2Ag2 complexes react with Ag(i) ions to give the corresponding Pt2Ag3 complexes containing Pt→Ag dative bonds. It became obvious that the existence of the C(ipso) atom in the chelate ligand is important as the driving force for forming Pt→Ag dative bonds. However, once the Pt2Ag3 complex is formed, the trapped Ag(i) ion is mainly stabilized by the Pt→Ag dative bonds, which are stronger than the Ag-C(ipso) bond. The trapped Ag(i) ion can be abstracted from the cavity selectively by adding an equivalent amount of chloride ion into the solution of Pt2Ag3 complexes to reproduce the original Pt2Ag2 complexes.

Different structural preference of Ag(I) and Au(I) in neutral and cationic luminescent heteropolynuclear platinum(II) complexes: Z (U)-shaped Pt2M2 type vs. trinuclear PtM2 type.

The reactions of monocationic Pt(II) complexes bearing N^C chelate ligands and Me2pzH, [Pt(N^C)(Me2pzH)2]PF6 (N^C = 2-phenylpyridinate (ppy(-)), 2-(2,4-difluorophenyl)pyridinate (dfppy(-)), benzo[h]quinolinate (bzq(-)); Me2pzH = 3,5-dimethylpyrazole), with Ag(I) ions gave Z (or U)-shaped neutral tetranuclear Pt2Ag2 complexes [Pt2Ag2(N^C)2(Me2pz)4], while those with Au(I) ions gave neutral trinuclear PtAu2 complexes [PtAu2(N^C)(Me2pz)3]. On the contrary, the reactions of the dicationic Pt(II) complex bearing a N^N chelate ligand and Me2pzH, [Pt(bpy)(Me2pzH)2](PF6)2 (bpy = 2,2'-bipyridine), with Ag(I) and Au(I) ions both gave Z (or U)-shaped dicationic tetranuclear Pt2M2 complexes, [Pt2M2(bpy)2(Me2pz)4](PF6)2 (M = Ag, Au). The structures of heteropolynuclear Pt(II) complexes were dominated by the nature of incorporated group 11 metal ions and the charge of complexes.